A broadly neutralizing anti-influenza antibody reveals ongoing capacity of haemagglutinin-specific memory B cells to evolve

• Published in: Nature communications 2016-09, Vol.7 (1), p.12780-12780, Article 12780
• Main Authors: Fu, Ying, Zhang, Zhen, Sheehan, Jared, Avnir, Yuval, Ridenour, Callie, Sachnik, Thomas, Sun, Jiusong, Hossain, M. Jaber, Chen, Li-Mei, Zhu, Quan, Donis, Ruben O., Marasco, Wayne A.
• Format: Article
• Language: English
• Subjects: 13/1; 13/31; 38/109; 631/1647/664/2228; 631/45/535/1267; 64/60; 692/699/255/1578; 82; 9/10; Animals; Antibodies; Antibodies, Neutralizing - immunology; Antibodies, Viral - immunology; Antibody Affinity; Antigens; B-Lymphocytes - physiology; Biological Evolution; Disease control; Epidemics; Epitope Mapping; Epitopes; Evolution; Gene Expression Regulation, Viral; Genes; Genomes; Hemagglutinin Glycoproteins, Influenza Virus - genetics; Humanities and Social Sciences; Humans; Immunologic Memory - genetics; Influenza; Influenza A virus - genetics; Influenza Vaccines - immunology; Influenza, Human - immunology; Influenza, Human - virology; Mice; Models, Molecular; multidisciplinary; Mutation; Orthomyxoviridae Infections - prevention & control; Orthomyxoviridae Infections - veterinary; Pandemics; Phylogeny; Plasma; Protein Binding; Protein Conformation; Science; Science (multidisciplinary); Vaccines; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms12780

Understanding the natural evolution and structural changes involved in broadly neutralizing antibody (bnAb) development holds great promise for improving the design of prophylactic influenza vaccines. Here we report an haemagglutinin (HA) stem-directed bnAb, 3I14, isolated from human memory B cells, that utilizes a heavy chain encoded by the IGHV3-30 germline gene. MAb 3I14 binds and neutralizes groups 1 and 2 influenza A viruses and protects mice from lethal challenge. Analysis of VH and VL germline back-mutants reveals binding to H3 and H1 but not H5, which supports the critical role of somatic hypermutation in broadening the bnAb response. Moreover, a single VLD94N mutation improves the affinity of 3I14 to H5 by nearly 10-fold. These data provide evidence that memory B cell evolution can expand the HA subtype specificity. Our results further suggest that establishing an optimized memory B cell pool should be an aim of ‘universal’ influenza vaccine strategies. A major goal of vaccine design is to protect against a broad range of pathogen strains. Here the authors isolate a new broadly neutralizing antibody against influenza haemagglutinin from human memory B cells, and identify mutations that increase and broaden the neutralization towards H5 HA subtype.